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Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant

Modeling Recent Human Evolutionin Mice by Expression of a SelectedEDAR Variant
Yana G. Kamberov,1,2,3,5,6,7,16 Sijia Wang,5,7,16,18 Jingze Tan,9 Pascale Gerbault,10 Abigail Wark,1 Longzhi Tan,5Yajun Yang,9 Shilin Li,9 Kun Tang,13 Hua Chen,14 Adam Powell,11 Yuval Itan,10,19 Dorian Fuller,12 Jason Lohmueller,5,20Junhao Mao,8,21 Asa Schachar,5,7 Madeline Paymer,5,7 Elizabeth Hostetter,5 Elizabeth Byrne,5 Melissa Burnett,2,4Andrew P. McMahon,8,22 Mark G. Thomas,10 Daniel E. Lieberman,6,17 Li Jin,
9,13,17,* Clifford J. Tabin,1,17Bruce A. Morgan,2,3,17,* and Pardis C. Sabeti5,7,15,17,
* 1Department of Genetics  2Department of DermatologyHarvard Medical School, Boston, MA 02115, USA  3Cutaneous Biology Research Center
4Department of DermatologyMassachusetts General Hospital, Boston, MA 02114, USA
5The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA6Department of Human Evolutionary Biology
7Center for Systems Biology, Department of Organismic and Evolutionary Biology
8Department of Molecular and Cellular BiologyHarvard University, Cambridge, MA 02138, USA
9MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200433, China
10Department of Genetics, Evolution and Environment
11UCL Genetics Institute (UGI)
12Institute of ArchaeologyUniversity College London, London WC1H 0PY, UK
13CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science,Shanghai 200031, China
14Department of Epidemiology  15Department of Immunology and Infectious DiseasesHarvard School of Public Health, Boston, MA 02115, USA

16These authors contributed equally to this work
17These authors contributed equally to this work and are cosenior authors
18Present address: Max Planck-CAS Paul Gerson Unna Research Group on Dermatogenomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
19Present address: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University,New York, NY, USA
20Present address: Department of Systems Biology Harvard Medical School, Boston, MA 02115, USA
21Present address: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA22Present address: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School Of Medicine,University of Southern California, CA 90089, USA
*Correspondence: lijin.fudan@gmail.com (L.J.), bruce.morgan@cbrc2.mgh.harvard.edu (B.A.M.), pardis@broadinstitute.org (P.C.S.)http://dx.doi.org/10.1016/j.cell.2013.01.016

An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genomewide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago.   Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.
本帖最后由 imvivi001 于 2017-3-26 13:11 编辑

Humans are unique among primates in having colonized nearlyevery corner of the world; consequently, niche-specific selective pressures likely helped shape the phenotypic variation currently evident in Homo sapiens. Identifying the genetic variants that underlie regional adaptations is thus central to understanding present-day human diversity, yet only a few adaptive traits have been elucidated. These include mutations in the Hemoglobin-Band Duffy antigen genes, driving resistance to P. falciparum and P. vivax malaria, respectively (Kwiatkowski,2005); mutations in lactase allowing some adult humans to digest milk after the domestication of milk-producing livestock(Enattah et al., 2002); and mutations in SLC24A5 and other genes driving variation in skin pigmentation (Lamason et al.,2005).
Although breakthroughs in genomic technology have facilitated the identification of hundreds of candidate genetic variants with evidence of recent positive natural selection, validation and characterization of putative genetic adaptations requires functional evidence linking genotypes to phenotypes that could affect an organism’s fitness (Akey, 2009). This is made difficult by experimental challenges in isolating the phenotypic effectsof candidate loci and by methodological limitations on the phenotypes that can be readily assessed in humans.  Accordingly,the best-characterized human adaptive alleles are typically those whose phenotypic outcomes are easily measured and strongly related to known genetic variation, such as lactase persistence or skin pigmentation. Many genes, however, have unknown or pleiotropic effects, making their adaptive advantage difficult to uncover (Sivakumaran et al., 2011).
A promising alternative to tackle these difficulties is to study the effects of candidate adaptive alleles in animal models. Although such models,particularly using mice, have been used extensively to study human disease alleles, they have not been used to model the subtle phenotypic changes expected to result from humanadaptive variation.A compelling candidate human adaptive allele to emerge from genome-wide scans is a derived coding variant of the EctodysplasinA (EDA) receptor (EDAR), EDARV370A (370A) (Sabetiet al., 2007; Grossman et al., 2010). Computational fine-mappingof the selection signal and the restricted occurrence of 370A inEast Asian and Native American populations have led to suggestions that 370A was selected in Asia (Bryk et al., 2008). In support of this hypothesis, 370A was shown to associate with increased scalp hair thickness and incisor tooth shoveling in multiple EastAsian populations (Fujimoto et al., 2008a, 2008b; Kimura et al.,2009; Park et al., 2012). However, because association studies quantify correlation rather than causation, it remains to be ascertained whether 370A is the genetic change driving the observed phenotypes.The biochemical properties of 370A support the possibility that the variant directly causes the associated phenotypes.
Structural models predict that V370A lies in the EDAR DeathDomain (DD) required for interaction with the downstream signal transducer EDARADD (Sabeti et al., 2007). Moreover, overexpression of 370A has been reported to upregulate downstreamNFkB signaling in vitro relative to 370V (Bryk et al., 2008; Mouet al., 2008). This finding suggested that a pre-existing mousemodel, in which the ancestral 370V allele is overexpressed,might provide insight into 370A’s phenotypic consequences(Headon and Overbeek, 1999; Mou et al., 2008).
Indeed, transgenicmice expressing multiple copies of 370V have thickerhair shafts as seen in humans with the 370A allele (Fujimotoet al., 2008a, 2008b; Mou et al., 2008). In addition, these animals exhibit increased mammary gland branching, enlarged mammary glands and hyperplastic sebaceous and Meibomian glands that secrete hydrophobic films as a barrier to water lossin the skin and eyes, respectively (Chang et al., 2009). These latter phenotypes led to the proposal that the 370A variantmay have been selected in response to cold and arid environmental conditions (Chang et al., 2009).
Evaluating which forces may have contributed to the spread of 370A requires knowledge of both the environmental context in which this variant was selected and its phenotypic effects. We therefore employed a multi-disciplinary approach to test the role of 370A in recent human evolution. This included modeling to reconstruct the evolutionary history of 370A, and a knockin mouse model to examine its direct phenotypic consequences.Analysis of the mouse knockin revealed phenotypes not previously reported in human genetic studies, which we further characterized in a Han Chinese cohort. This work highlights the utility of modeling nonpathological human genetic variation in mice, providing a framework for assessing other candidate adaptive human alleles.
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An Ancient Asian Origin for 370ASpatially explicit simulation, haplotype,and maximum likelihood analyses suggestthat 370A originated once in centralChina more than 30,000 years BP witha selective coefficient that is one of thehighest measured in human populations. Our results are consistentwith previous inferences that 370A must have arisen prior to15,000 BP (Bryk et al., 2008; Peter et al., 2012) and the firstpeopling of the Americas (Goebel et al., 2008; O’Rourke andRaff, 2010) but also suggest that the allele likely emerged inEast Asia even earlier. It should be noted that haplotype-basedmethods, such as that used by Bryk and colleagues (Bryket al., 2008) assume recombination occurs between distincthaplotypes. However, in a case of rapid local fixation, as is likelyfor a strongly selected and semidominant allele like 370A,recombination of the selected haplotype with itself would bemasked, reducing the observed number of recombinations andleading to underestimation of the time of origin (Figure S7).Thus, our findings shift the context in which to consider theselective forces that could have acted on 370A.

2017-3-26 14:45

Pleiotropic Effects and Potential Selective ForcesFavoring the 370A

AlleleOur study provides evidence that 370A was selected in EastAsia, but the question of which of its observed pleiotropic phenotypeswere adaptations and which were exaptations remains.One possibility is that selection favored individuals with anFigure 5. 370A Reduces the Size of the Mammary Fat Pad and Increases Mammary Gland Branch Density(A–D) Whole mount preparations of stained mammary glands. (A) Gland area (dotted line) and fat pad area (dashed line) are quantified from the main lactiferousduct (arrow head). Representative images are shown of 370V (B), 370V/370A (C), and 370A (D).(E and F) Average branch density (±SEM) (E) and mean fat pad area (±SEM) (F) are shown.

Significance levels by ANOVA post hoc tests: p < 0.05 (*), p < 0.01 (**), p < 0.001 (***). See also Table S5.Cell 152, 691–702, February 14, 2013 a2013 Elsevier Inc. 697increased number of eccrine glands. A high density of eccrineglands is a key hominin adaptation that enables efficient evapotraspirationduring vigorous activities such as long-distancewalking and running (Carrier et al., 1984; Bramble and Lieberman,2004). An increased density of eccrine glands in 370Acarriers might have been advantageous for East Asian hunter-gatherersduring warm and humid seasons, which hinderevapotranspiration.Geological records indicate that China was relatively warmand humid between 40,000 and 32,000 years ago, but between32,000 and 15,000 years ago the climate became coolerand drier before warming again at the onset of the Holocene(Wang et al., 2001; Yuan et al., 2004). Throughout this timeperiod, however, China may have remained relatively humiddue to varying contribution from summer and winter monsoons Figure 6. 370AIncreases the Number of Eccrine Sweat Glands inMice(A–C) Representative whole-mount preparations of the volar hindfoot skin of370V (A), 370V/370A (B), and 370A (C) mice. Gland ducts appear as thin bluetubes emerging from inside the footpads (FP).(D–F) Detail view of FP-3 from 370V (D), 370V/370A (E), and 370A (F) mice.(G) Quantification of average gland number per FP (±SEM) across the threegenotypes.(H) 370A rescues the decrease in eccrine gland number in 379K heterozygousmutant mice. Average gland number per FP is shown (±SEM).
Significance of differences by ANOVA post hoc tests: p < 0.05 (*), p < 0.01 (**),p < 0.001 (***).
All experiments were carried out on fifth generation FVB backcross animals,but those shown in (H) were a FVB by C3HeB/FeJ outcross. The difference ingenetic background accounts for the difference in eccrine gland numberbetween wild-type animals in (G and H). See also Table S5.Figure 7. 370A Is Associated with Increased Eccrine Sweat GlandDensity in Humans(A and B) Representative cropped active sweat gland images of the digit tipsof a 370V/370A heterozygous (A) and a 370A homozygous (B) individual.Cropped size is 1.30cm2.(C) Active sweat gland density is significantly increased in 370A individuals.Average sweat gland density is shown for each genotype (±SEM). Significanceof difference by two tailed t test: p < 0.05 (*). See also Table S6.698 Cell 152, 691–702, February 14, 2013 a2013 Elsevier Inc.(Sun et al., 2012). High humidity, especially in the summers, mayhave provided a seasonally selective advantage for individualsbetter able to functionally activate more eccrine glands andthus sweat more effectively (Kuno, 1956).

To explore this hypothesis,greater precision on when and where the allele was underselection—perhaps using ancient DNA sources—in conjunctionwith more detailed archaeological and climatic data are needed.Alternatively, another phenotype, such as mammary glandbranching or fat pad size could have been adaptive. Theincreased branching of 370A mouse mammary glands and theimportance of mammary tissue in evolutionary fitness (Andersonet al., 1983; Oftedal, 2002) make this organ an interesting candidate.Alterations in gland structure have been reported to disruptlactation in mice (Ramanathan et al., 2007), suggesting a functionalconsequence for this change. Unfortunately, it is notpossible to assess mammary gland branching in living humans,highlighting the importance of animal models. Reports of smallerbreast size in East Asian women (Maskarinec et al., 2001; Chenet al., 2004) are notable in light of the effects of 370A on fat padsize and the importance of breast morphology in human matepreference (Furnham et al., 1998, 2006; Dixson et al., 2011).Further analysis of the functional implications of 370A in themouse and development of methods to assay these phenotypesin humans are critical to evaluate such hypotheses and also toanalyze additional potential 370A phenotypes yet to be investigated,such as those linked to differential susceptibility to respiratorydisease (Clarke et al., 1987; Mauldin et al., 2009).In light of 370A’s pleiotropy, it is possible that selection actedon multiple traits. The tendency to seek a single driving characteris underlain by the perception that pleiotropic changes areinherently disadvantageous. Evolution is believed to proceedprimarily through mutations in gene regulatory regions ratherthan exons because this reduces pleiotropic effects (King andWilson, 1975; Stern, 2000; Carroll, 2008). From the perspectiveof this model, a specific effect of 370A’s pleiotropic consequenceswas favored under the conditions present in East Asiaand conferred an advantage with other neutral or deleterioustraits hitchhiking along with the selected trait.

However, the largecoefficient of selection on 370A contrasts with the relativelymodest magnitude of structural changes on any one affectedtrait and suggests alternative interpretations. One possibility isthat the effects of 370A were magnified by coselection onanother variant. For example, a coding variant of the relatedEDA2R gene affects human hair and has swept to fixation inEast Asia (Sabeti et al., 2007; Prodi et al., 2008).Alternatively, it could be precisely the pleiotropic nature of370A that allowed multiple distinct selective forces to act onthis variant over its long history, when many of the postulatedselective pressures such as temperature and humidity changeddramatically. The fact that EDAR acts mostly on ectodermalappendages and that the phenotypic effects of the 370A alleleare not extreme reduces the costs of pleiotropy and would facilitatethis process. Thus, what were initially neutral changes insome appendages driven by 370A would gain adaptive signifi-cance in the face of new selective pressures. It is worth notingthat largely invisible structural changes resulting from the 370Aallele that might confer functional advantage, such as increasedeccrine gland number, are directly linked to visually obvioustraits such as hair phenotypes and breast size. This createsconditions in which biases in mate preference could rapidlyevolve and reinforce more direct competitive advantages.Consequently, the cumulative selective force acting over timeon diverse traits caused by a single pleiotropic mutation couldhave driven the rise and spread of 370A.
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